The present invention relates to ether compounds and pharmaceutically acceptable salts thereof; methods for synthesizing the ether compounds; compositions comprising an ether compound or a pharmaceutically acceptable salt thereof; and methods for treating or preventing a disease or disorder selected from the group consisting of a cardiovascular disease, dyslipidemia, dyslipoproteinemia, a disorder of glucose metabolism, Alzheimer""s Disease, Syndrome X; a peroxisome proliferator activated receptor-associated disorder, septicemia, a thrombotic disorder, obesity, pancreatitis, hypertension, renal disease, cancer, inflammation, and impotence, comprising administering a therapeutically effective amount of a composition comprising an ether compound or a pharmaceutically acceptable salt thereof. The ether compounds and compositions of the invention may also be used to reduce the fat content of meat in livestock and reduce the cholesterol content of eggs.
Obesity, hyperlipidemia, and diabetes have been shown to play a casual role in atherosclerotic cardiovascular diseases, which currently account for a considerable proportion of morbidity in Western society. Further, one human disease, termed xe2x80x9cSyndrome Xxe2x80x9d or xe2x80x9cMetabolic Syndromexe2x80x9d, is manifested by defective glucose metabolism (insulin resistance), elevated blood pressure (hypertension), and a blood lipid imbalance (dyslipidemia). See e.g. Reaven, 1993, Annu. Rev. Med. 44:121-131.
The evidence linking elevated serum cholesterol to coronary heart disease is overwhelming. Circulating cholesterol is carried by plasma lipoproteins, which are particles of complex lipid and protein composition that transport lipids in the blood. Low density lipoprotein (LDL) and high density lipoprotein (HDL) are the major cholestrol-carrier proteins. LDL are believed to be responsible for the delivery of cholesterol from the liver, where it is synthesized or obtained from dietary sources, to extrahepatic tissues in the body. The term xe2x80x9creverse cholesterol transportxe2x80x9d describes the transport of cholesterol from extrahepatic tissues to the liver, where it is catabolized and eliminated. It is believed that plasma HDL particles play a major role in the reverse transport process, acting as scavengers of tissue cholesterol. HDL is also responsible for the removal non-cholesterol lipid, oxidized cholesterol and other oxidized products from the bloodstream.
Atherosclerosis, for example, is a slowly progressive disease characterized by the accumulation of cholesterol within the arterial wall. Compelling evidence supports the belief that lipids deposited in atherosclerotic lesions are derived primarily from plasma apolipoprotein B (apo B)-containing lipoproteins, which include chylomicrons, CLDL, IDL and LDL. The apo B-containing lipoprotein, and in particular LDL, has popularly become known as the xe2x80x9cbadxe2x80x9d cholesterol. In contrast, HDL serum levels correlate inversely with coronary heart disease. Indeed, high serum levels of HDL is regarded as a negative risk factor. It is hypothesized that high levels of plasma HDL is not only protective against coronary artery disease, but may actually induce regression of atherosclerotic plaque (e.g., see Badimon et al., 1992, Circulation 86:(Suppl. III)86-94; Dansky and Fisher, 1999, Circulation 100:1762-3.). Thus, HDL has popularly become known as the xe2x80x9cgoodxe2x80x9d cholesterol.
The fat-transport system can be divided into two pathways: an exogenous one for cholesterol and triglycerides absorbed from the intestine and an endogenous one for cholesterol and triglycerides entering the bloodstream from the liver and other non-hepatic tissue.
In the exogenous pathway, dietary fats are packaged into lipoprotein particles called chylomicrons, which enter the bloodstream and deliver their triglycerides to adipose tissue for storage and to muscle for oxidation to supply energy. The remnant of the chylomicron, which contains cholesteryl esters, is removed from the circulation by a specific receptor found only on liver cells. This cholesterol then becomes available again for cellular metabolism or for recycling to extrahepatic tissues as plasma lipoproteins.
In the endogenous pathway, the liver secretes a large, very-low-density lipoprotein particle (VLDL) into the bloodstream. The core of VLDL consists mostly of triglycerides synthesized in the liver, with a smaller amount of cholesteryl esters either synthesized in the liver or recycled from chylomicrons. Two predominant proteins are displayed on the surface of VLDL, apolipoprotein B-100 (apo B-100) and apolipoprotein E (apo E), although other apolipoproteins are present, such as apolipoprotein CIII (apo CIII) and apolipoprotein CII (apo CII). When a VLDL reaches the capillaries of adipose tissue or of muscle, its triglyceride is extracted. This results in the formation of a new kind of particle called intermediate-density lipoprotein (IDL) or VLDL remnant, decreased in size and enriched in cholesteryl esters relative to a VLDL, but retaining its two apoproteins.
In human beings, about half of the IDL particles are removed from the circulation quickly, generally within two to six hours of their formation. This is because IDL particles bind tightly to liver cells, which extract IDL cholesterol to make new VLDL and bile acids. The IDL not taken up by the liver is catabolized by the hepatic lipase, an enzyme bound to the proteoglycan on liver cells. Apo E dissociates from IDL as it is transformed to LDL. Apo B-100 is the sole protein of LDL.
Primarily, the liver takes up and degrades circulating cholesterol to bile acids, which are the end products of cholesterol metabolism. The uptake of cholesterol-containing particles is mediated by LDL receptors, which are present in high concentrations on hepatocytes. The LDL receptor binds both apo E and apo B-100 and is responsible for binding and removing both IDL and LDL from the circulation. IN addition, remnant receptors are responsible for clearing chylomicrons and VLDL remnants i.e., IDL). However, the affinity of apo E for the LDL receptor is greater than that of apo B-100. As a result, the LDL particles have a much longer circulating life span than IDL particles; LDL circulates for an average of two and a half days before binding to the LDL receptors in the liver and other tissues. High serum levels of LDL, the xe2x80x9cbadxe2x80x9d cholesterol, are positively associated with coronary heart disease. For example, in atherosclerosis, cholesterol derived from circulating LDL accumulates in the walls of arteries. This accumulation forms bulky plaques that inhibit the flow of blood until a clot eventually forms, obstructing an artery and causing a heart attack or stroke.
Ultimately, the amount of intracellular cholesterol liberated from the LDL controls cellular cholesterol metabolism. The accumulation of cellular cholesterol derived from VLDL and LDL controls three processes. First, it reduces the cell""s ability to make its own cholesterol by turning off the synthesis of HMGCoA reductase, a key enzyme in the cholesterol biosynthetic pathway. Second, the incoming LDL-derived cholesterol promotes storage of cholesterol by the action of ACAT, the cellular enzyme that converts cholesterol into cholesteryl esters that are deposited in storage droplets. Third, the accumulation of cholesterol within the cell drives a feedback mechanism that inhibits cellular synthesis of new LDL receptors. Cells, therefore, adjust their complement of LDL receptors so that enough cholesterol is brought in to meet their metabolic needs, without overloading (for a review, see Brown and Goldstein, In, The Pharmacological Basis Of Therapeutics, 8th Ed., Goodman and Gilman, Pergaman Press, NY, 1990, Ch. 36, pp. 874-896).
High levels of apo B-containing lipoproteins can be trapped in the subendothelial space of an artery and undergo oxidation. The oxidized lipoprotein is recognized by scavenger receptors on macrophages. Binding of oxidized lipoprotein to the scavenger receptors can enrich the macrophages with cholesterol and cholesteryl esters independently of the LDL receptor. Macrophages can also produce cholesteryl esters by the action of ACAT. LDL can also be complexed to a high molecular weight glycoprotein called apolipoprotein(a), also known as apo(a), through a disulfide bridge. The LDL-apo(a) complex is known as Lipoprotein(a) or Lp(a). Elevated levels of Lp(a) are detrimental, having been associated with atherosclerosis, coronary heart disease, myocardial infarcation, stroke, cerebral infarction, and restenosis following angioplasty.
Peripheral (non-hepatic) cells predominantly obtain their cholesterol from a combination of local synthesis and uptake of preformed sterol from VLDL and LDL. Cells expressing scavenger receptors, such as macrophages and smooth muscle cells, can also obtain cholesterol from oxidized apo B-containing lipoproteins. In contrast, reverse cholesterol transport (RCT) is the pathway by which peripheral cell cholesterol can be returned to the liver for recycling to extrahepatic tissues, hepatic storage, or excretion into the intestine in bile. The RCT pathway represents the only means of eliminating cholesterol from most extrahepatic tissues and is crucial to maintenance of the structure and function of most cells in the body.
The enzyme in blood involved in the RCT pathway, lecithin:cholesterol acyltransferase (LCAT), converts cell-derived cholesterol to cholesteryl esters, which are sequestered in HDL destined for removal. LCAT is produced mainly in the liver and circulates in plasma associated with the HDL fraction. Cholesterol ester transfer protein (CETP) and another lipid transfer protein, phospholipid transfer protein (PLTP), contribute to further remodeling the circulating HDL population (see for example Bruce et al., 1998, Annu. Rev. Nutr. 18:297-330). PLTP supplies lecithin to HDL, and CETP can move cholesteryl ester made by LCAT to other lipoproteins, particularly apoB-containing lipoproteins, such as VLDL. HDL triglyceride can be catabolized by the extracellular hepatic triglyceride lipase, and lipoprotein cholesterol is removed by the liver via several mechanisms.
Each HDL particle contains at least one molecule, and usually two to four molecules, of apolipoprotein (apo A-I). Apo A-I is synthesized by the liver and small intestine as preproapolipoprotein which is secreted as a proprotein that is rapidly cleaved to generate a mature polypeptide having 243 amino acid residues. Apo A-I consists mainly of a 22 amino acid repeating segment, spaced with helix-breaking proline residues. Apo A-I forms three types of stable structures with lipids: small, lipid-poor complexes referred to as pre-beta-1 HDL; flattened discoidal particles, referred to as pre-beta-2 HDL, which contain only polar lipids (e.g., phospholipid and cholesterol); and spherical particles containing both polar and nonpolar lipids, referred to as spherical or mature HDL (HDL3 and HDL2). Most HDL in the circulating population contains both apo A-I and apo A-II, a second major HDL protein. This apo A-I- and apo A-II-containing fraction is referred to herein as the AI/AII-HDL fraction of HDL. But the fraction of HDL containing only apo A-I, referred to herein as the AI-HDL fraction, appears to be more effective in RCT. Certain epidemiologic studies support the hypothesis that the AI-HDL fraction is antiartherogenic (Parra et al., 1992, Arterioscler. Thromb. 12:701-707; Decossin et al., 1997, Eur. J. Clin. Invest. 27:299-307).
Although the mechanism for cholesterol transfer from the cell surface is unknown, it is believed that the lipid-poor complex, pre-beta-1 HDL, is the preferred acceptor for cholesterol transferred from peripheral tissue involved in RCT. Cholesterol newly transferred to pre-beta-1 HDL from the cell surface rapidly appears in the discoidal pre-beta-2 HDL. PLTP may increase the rate of disc formation (Lagrost et al., 1996, J. Biol. Chem. 271:19058-19065), but data indicating a role for PLTP in RCT is lacking. LCAT reacts preferentially with discoidal and spherical HDL, transferring the 2-acyl group of lecithin or phosphatidylethanolamine to the free hydroxyl residue of fatty alcohols, particularly cholesterol, to generate cholesteryl esters (retained in the HDL) and lysolecithin. The LCAT reaction requires an apoliprotein such apo A-I or apo A-IV as an activator. ApoA-I is one of the natural cofactors for LCAT. The conversion of cholesterol to its HDL-sequestered ester prevents re-entry of cholesterol into the cell, resulting in the ultimate removal of cellular cholesterol. Cholesteryl esters in the mature HDL particles of the AI-HDL fraction are removed by the liver and processed into bile more effectively than those derived from the AI/AII-HDL fraction. This may be due, in part, to the more effective binding of AI-HDL to the hepatocyte membrane. Several HDL receptor receptors have been identified, the most well characterized of which is the scavenger receptor class B, type I (SR-BI) (Acton et al., 1996, Science 271:518-520). The SR-BI is expressed most abundantly in steroidogenic tissues (e.g., the adrenals), and in the liver (Landshulz et al., 1996, J. Clin. Invest. 98:984-995; Rigotti et al., 1996, J. Biol. Chem. 271:33545-33549). Other proposed HDL receptors include HB1 and HB2 (Hidaka and Fidge, 1992, Biochem J. 15:161-7; Kurata et al., 1998, J. Atherosclerosis and Thrombosis 4:112-7).
While there is a consensus that CETP is involved in the metabolism of VLDL- and LDL-derived lipids, its role in RCT remains controversial. However, changes in CETP activity or its acceptors, VLDL and LDL, play a role in xe2x80x9cremodelingxe2x80x9d the HDL population. For example, in the absence of CETP, the HDL becomes enlarged particles that are poorly removed from the circulation (for reviews on RCT and HDLs, see Fielding and Fielding, 1995, J. Lipid Res. 36:211-228; Barrans et al., 1996, Biochem. Biophys. Acta. 1300:73-85; Hirano et al., 1997, Arterioscler. Thromb. Vasc. Biol. 17:1053-1059).
HDL is not only involved in the reverse transport of cholesterol, but also plays a role in the reverse transport of other lipids, i.e., the transport of lipids from cells, organs, and tissues to the liver for catabolism and excretion. Such lipids include sphingomyelin, oxidized lipids, and lysophophatidylcholine. For example, Robins and Fasulo (1997, J. Clin. Invest. 99:380-384) have shown that HDL stimulates the transport of plant sterol by the liver into bile secretions.
Peroxisome proliferators are a structurally diverse group of compounds that, when administered to rodents, elicit dramatic increases in the size and number of hepatic and renal peroxisomes, as well as concomitant increases in the capacity of peroxisomes to metabolize fatty acids via increased expression of the enzymes required for the xcex2-oxidation cycle (Lazarow and Fujiki, 1985, Ann. Rev. Cell Biol. 1:489-530; Vamecq and Draye, 1989, Essays Biochem. 24:1115-225; and Nelali et al., 1988, Cancer Res. 48:5316-5324). Chemicals included in this group are the fibrate class of hypolipidermic drugs, herbicides, and phthalate plasticizers (Reddy and Lalwani, 1983, Crit. Rev. Toxicol. 12:1-58). Peroxisome proliferation can also be elicited by dietary or physiological factors, such as a high-fat diet and cold acclimatization.
Insight into the mechanism whereby peroxisome proliferators exert their pleiotropic effects was provided by the identification of a member of the nuclear hormone receptor superfamily activated by these chemicals (Isseman and Green, 1990, Nature 347:645-650). This receptor, termed peroxisome proliferator activated receptor xcex1 (PPARxcex1), was subsequently shown to be activated by a variety of medium and long-chain fatty acids. PPARxcex1 activates transcription by binding to DNA sequence elements, termed peroxisome proliferator response elements (PPRE), in the form of a heterodimer with the retinoid X receptor (RXR). RXR is activated by 9-cis retinoic acid (see Kliewer et al., 1992, Nature 358:771-774; Gearing et al., 1993, Proc. Natl. Acad. Sci. USA 90:1440-1444, Keller et al., 1993, Proc. Natl. Acad. Sci. USA 90:2160-2164; Heyman et al., 1992, Cell 68:397-406, and Levin et al., 1992, Nature 355:359-361). Since the discovery of PPARxcex1, additional isoforms of PPAR have been identified, e.g., PPARxcex2, PPARxcex3 and PPARxcex4, which are have similar functions and are similarly regulated.
PPREs have been identified in the enhancers of a number of genes encoding proteins that regulate lipid metabolism. These proteins include the three enzymes required for peroxisomal xcex2-oxidation of fatty acids; apolipoprotein A-I; medium-chain acyl-CoA dehydrogenase, a key enzyme in mitochondrial xcex2-oxidation; and aP2, a lipid binding protein expressed exclusively in adipocytes (reviewed in Keller and Whali, 1993, TEM, 4:291-296;
see also Staels and Auwerx, 1998, Atherosclerosis 137 Suppl:S19-23). The nature of the PPAR target genes coupled with the activation of PPARs by fatty acids and hypolipidemic drugs suggests a physiological role for the PPARs in lipid homeostasis.
Pioglitazone, an antidiabetic compound of the thiazolidinedione class, was reported to stimulate expression of a chimeric gene containing the enhancer/promoter of the lipid-binding protein aP2 upstream of the chloroamphenicol acetyl transferase reporter gene (Harris and Kletzien, 1994, Mol. Pharmacol. 45:439-445). Deletion analysis led to the identification of an approximately 30 bp region responsible for pioglitazone responsiveness. In an independent study, this 30 bp fragment was shown to contain a PPRE (Tontonoz et al., 1994, Nucleic Acids Res. 22:5628-5634). Taken together, these studies suggested the possibility that the thiazolidinediones modulate gene expression at the transcriptional level through interactions with a PPAR and reinforce the concept of the interrelatedness of glucose and lipid metabolism.
In the past two decades or so, the segregation of cholesterolemic compounds into HDL and LDL regulators and recognition of the desirability of decreasing blood levels of the latter has led to the development of a number of drugs. However, many of these drugs have undesirable side effects and/or are contraindicated in certain patients, particularly when administered in combination with other drugs.
Bile-acid-binding resins are a class of drugs that interrupt the recycling of bile acids from the intestine to the liver. Examples of bile-acid-binding resins are cholestyramine (QUESTRAN LIGHT, Bristol-Myers Squibb), and colestipol hydrochloride (COLESTID, Pharmacia and Upjohn Company). When taken orally, these positively charged resins bind to negatively charged bile acids in the intestine. Because the resins cannot be absorbed from the intestine, they are excreted, carrying the bile acids with them. The use of such resins, however, at best only lowers serum cholesterol levels by about 20%. Moreover, their use is associated with gastrointestinal side-effects, including constipation and certain vitamin deficiencies. Moreover, since the resins bind to drugs, other oral medications must be taken at least one hour before or four to six hours subsequent to ingestion of the resin, complicating heart patients"" drug regimens.
The statins are inhibitors of cholesterol synthesis. Sometimes, the statins are used in combination therapy with bile-acid-binding resins. Lovastatin (MEVACOR, Merck and Co., Inc.), a natural product derived from a strain of Aspergillus; pravastatin (PRAVACHOL, Bristol-Myers Squibb Co.); and atorvastatin (LIPITOR, Warner Lambert) block cholesterol synthesis by inhibiting HMGCoA, the key enzyme involved in the cholesterol biosynthetic pathway. Lovastatin significantly reduces serum cholesterol and LDL-serum levels. It also slows progression of coronary atherosclerosis. However, serum HDL levels are only slightly increased following lovastatin administration. The mechanism of the LDL-lowering effect may involve both reduction of VLDL concentration and induction of cellular expression of LDL-receptor, leading to reduced production and/or increased catabolism of LDL. Side effects, including liver and kidney dysfunction are associated with the use of these drugs.
Niacin, also known as nicotinic acid, is a water-soluble vitamin B-complex used as a dietary supplement and antihyperlipidemic agent. Niacin diminishes production of VLDL and is effective at lowering LDL. It is used in combination with bile-acid-binding resins. Niacin can increase HDL when administered at therapeutically effective doses; however, its usefulness is limited by serious side effects.
Fibrates are a class of lipid-lowering drugs used to treat various forms of hyperlipidemia, elevated serum triglycerides, which may also be associated with hypercholesterolemia. Fibrates appear to reduce the VLDL fraction and modestly increase HDL; however, the effects of these drugs on serum cholesterol is variable. In the United States, fibrates have been approved for use as antilipidemic drugs, but have not received approval as hypercholesterolemia agents. For example, clofibrate (ATROMID-S, Wyeth-Ayerst Laboratories) is an antilipidemic agent that acts to lower serum triglycerides by reducing the VLDL fraction. Although ATROMID-S may reduce serum cholesterol levels in certain patient subpopulations, the biochemical response to the drug is variable, and is not always possible to predict which patients will obtain favorable results. ATROMID-S has not been shown to be effective for prevention of coronary heart disease. The chemically and pharmacologically related drug, gemfibrozil (LOPID, Parke-Davis), is a lipid regulating agent which moderately decreases serum triglycerides and VLDL cholesterol. LOPID also increases HDL cholesterol, particularly the HDL2 and HDL3 subfractions, as well as both the AI/AII-HDL fraction. However, the lipid response to LOPID is heterogeneous, especially among different patient populations. Moreover, while prevention of coronary heart disease was observed in male patients between the ages of 40 and 55 without history or symptoms of existing coronary heart disease, it is not clear to what extent these findings can be extrapolated to other patient populations (e.g., women, older and younger males). Indeed, no efficacy was observed in patients with established coronary heart disease. Serious side-effects are associated with the use of fibrates, including toxicity; malignancy, particularly malignancy of gastrointestinal cancer; gallbladder disease; and an increased incidence in non-coronary mortality. These drugs are not indicated for the treatment of patients with high LDL or low HDL as their only lipid abnormality.
Oral estrogen replacement therapy may be considered for moderate hypercholesterolemia in post-menopausal women. However, increases in HDL may be accompanied with an increase in triglycerides. Estrogen treatment is, of course, limited to a specific patient population, postmenopausal women, and is associated with serious side effects, including induction of malignant neoplasms; gall bladder disease; thromboembolic disease; hepatic adenoma; elevated blood pressure; glucose intolerance; and hypercalcemia.
Long chain carboxylic acids, particularly long chain xcex1,xcfx89-dicarboxylic acids with distinctive substitution patterns, and their simple derivatives and salts, have been disclosed for treating atherosclerosis, obesity, and diabetes (See, e.g., Bisgaier et al., 1998, J. Lipid Res. 39:17-30, and references cited therein; International Patent Publication WO 98/30530; U.S. Pat. No. 4,689,344; International Patent Publication WO 99/00116; and U.S. Pat. No. 5,756,344). However, some of these compounds, for example the xcex1,xcfx89-dicarboxylic acids substituted at their xcex1,xcex1xe2x80x2-carbons (U.S. Pat. No. 3,773,946), while having serum triglyceride and serum cholesterol-lowering activities, have no value for treatment of obesity and hypercholesterolemia (U.S. Pat. No. 4,689,344).
U.S. Pat. No. 4,689,344 discloses xcex2,xcex2,xcex2xe2x80x2,xcex2xe2x80x2-tetrasubstituted-xcex1,xcfx89-alkanedioic acids that are optionally substituted at their xcex1,xcex1,xcex1xe2x80x2,xcex1xe2x80x2 positions, and alleges that they are useful for treating obesity, hyperlipidemia, and diabetes. According to this reference, both triglycerides and cholesterol are lowered significantly by compounds such as 3,3,14,14-tetramethylhexadecane-1,16-dioic acid. U.S. Pat. No. 4,689,344 further discloses that the xcex2,xcex2,xcex2xe2x80x2,xcex2xe2x80x2-tetramethyl-alkanediols of U.S. Pat. No. 3,930,024 also are not useful for treating hypercholesterolemia or obesity.
Other compounds are disclosed in U.S. Pat. No. 4,711,896. In U.S. Pat. No. 5,756,544, xcex1,xcfx89-dicarboxylic acid-terminated dialkane ethers are disclosed to have activity in lowering certain plasma lipids, including Lp(a), triglycerides, VLDL-cholesterol, and LDL-cholesterol, in animals, and elevating others, such as HDL-cholesterol. The compounds are also stated to increase insulin sensitivity. In U.S. Pat. No. 4,613,593, phosphates of dolichol, a polyprenol isolated from swine liver, are stated to be useful in regenerating liver tissue, and in treating hyperuricuria, hyperlipemia, diabetes, and hepatic diseases in general.
U.S. Pat. No. 4,287,200 discloses azolidinedione derivatives with antidiabetic, hypolipidemic, and anti-hypertensive properties. However, these administration of these compounds to patients can produce side effects such as bone marrow depression, and both liver and cardiac cytotoxicity. Further, the compounds disclosed by U.S. Pat. No. 5 4,287,200 stimulate weight gain in obese patients.
It is clear that none of the commercially available cholesterol management drugs has a general utility in regulating lipid, lipoprotein, insulin and glucose levels in the blood. Thus, compounds that have one or more of these utilities are clearly needed. Further, there is a clear need to develop safer drugs that are efficacious at lowering serum cholesterol, increasing HDL serum levels, preventing coronary heart disease, and/or treating existing disease such as atherosclerosis, obesity, diabetes, and other diseases that are affected by lipid metabolism and/or lipid levels. There is also is a clear need to develop drugs that may be used with other lipid-altering treatment regimens in a synergistic manner. There is still a further need to provide useful therapeutic agents whose solubility and Hydrophile/Lipophile Balance (HLB) can be readily varied.
Citation or identification of any reference in Section 2 of this application is not an admission that such reference is available as prior art to the present invention.
In one embodiment, the invention provides novel compounds having the general formula I: 
and pharmaceutically acceptable salts thereof, wherein:
R1, R2, R3, and R4 are independently selected from the group consisting of (C-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, and benzyl; or R1, R2, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group; or R3, R4, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group; or R1, R2, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group and R3, R4, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group, with the proviso that none of R1, R2, R3, or R4 is xe2x80x94(CH2)0-4Cxe2x89xa1CH;
n and m are independent integers ranging from 0 to 4;
K1 and K2 are independently selected from the group consisting of xe2x80x94CH2OH, xe2x80x94C(O)OH, xe2x80x94CHO, xe2x80x94C(O)OR5, xe2x80x94OC(O)R5, xe2x80x94SO3H, 
R5 is selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, and benzyl;
each R6 is independently selected from the group consisting of H, (C1-C6)alkyl, (C2-C6)alkenyl, and (C2-C6)alkynyl;
R7 is selected from the group consisting of H, (C1-C6)alkyl, (C2-C6)alkenyl, and (C2-C6)alkynyl; and
with the proviso that when n and m are both 1 or both 0, then K1 and K2 are not both X, wherein X is selected from the group consisting of xe2x80x94COOH, xe2x80x94C(O)OR5, 
In another embodiment, the invention provides novel compounds having the general formula I, and pharmaceutically acceptable salts thereof, wherein:
R1, R2, R3, and R4 are independently selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, and benzyl; or R1, R2, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group; or R3, R4, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group; or R1, R2, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group and R3, R4, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group, with the proviso that none of R1, R2, R3, or R4 is xe2x80x94(CH2)0-4Cxe2x89xa1CH;
n and m are independent integers ranging from 0 to 4;
K1 and K2 are independently selected from the group consisting of xe2x80x94CH2OH, xe2x80x94C(O)OH, xe2x80x94CHO, xe2x80x94C(O)OR5, xe2x80x94OC(O)R5, xe2x80x94SO3H, 
R5 is selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, and benzyl;
each R6 is independently selected from the group consisting of H, (C1-C6)alkyl, (C2-C6)alkenyl, and (C2-C6)alkynyl;
R7 is selected from the group consisting of H, (C1-C6)alkyl, (C2-C6)alkenyl, and (C2-C6)alkynyl; and
with the proviso that when n and m are both 1 or both 0, then K1 and K2 are not both X, wherein X is selected from the group consisting of xe2x80x94COOH, xe2x80x94C(O)OR5, 
In yet another embodiment, the invention provides novel compounds having the general formula I, and pharmaceutically acceptable salts thereof, wherein:
R1, R2, R3, and R4 are independently selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, and benzyl; or R1, R2, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group; or R3, R4, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group; or R1, R2, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group and R3, R4, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group, with the proviso that none of R1, R2, R3, or R4 is xe2x80x94(CH2)0-4Cxe2x89xa1CH;
n and m are independent integers ranging from 0 to 4;
K1 is selected from the group consisting of xe2x80x94CH2OH, xe2x80x94OC(O)R5, xe2x80x94CHO, xe2x80x94SO3H, 
K2 is selected from the group consisting of xe2x80x94CH2OH, xe2x80x94C(O)OH, xe2x80x94CHO, xe2x80x94C(O)OR5, xe2x80x94OC(O)R5, xe2x80x94SO3H, 
R5 is selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, and benzyl;
each R6 is independently selected from the group consisting of H, (C1-C6)alkyl, (C2-C6)alkenyl, and (C2-C6)alkynyl;
R7 is selected from the group consisting of H, (C1-C6)alkyl, (C2-C6)alkenyl, and (C2-C6)alkynyl; and
with the proviso that when n and m are both 1 or both 0, then K1 and K2 are not both X, wherein X is selected from the group consisting of xe2x80x94COOH, xe2x80x94C(O)OR5, 
In yet another embodiment, the invention provides novel compounds having the general formula I and pharmaceutically acceptable salts thereof, wherein:
R1, R2, R3, and R4 are independently selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, and benzyl; or R1, R2, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group; or R3, R4, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group; or R1, R2, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group and R3, R4, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group, with the proviso that none of R1, R2, R3, or R4 is xe2x80x94(CH2)0-4Cxe2x89xa1CH;
n and m are independent integers ranging from 0 to 4;
K1 and K2 are independently selected from the group consisting of xe2x80x94CH2OH, xe2x80x94OC(O)R5, xe2x80x94CHO, xe2x80x94SO3H, 
R5 is selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, and benzyl;
each R6 is independently selected from the group consisting of H, (C1-C6)alkyl, (C2-C6)alkenyl, and (C2-C6)alkynyl;
R7 is selected from the group consisting of H, (C1-C6)alkyl, (C2-C6)alkenyl, and (C2-C6)alkynyl; and
with the proviso that when n and m are both 1 or both 0, then K1 and K2 are not both X, wherein X is selected from the group consisting of xe2x80x94COOH, xe2x80x94C(O)OR5, 
In still another embodiment, the invention provides novel compounds having the general formula I, and pharmaceutically acceptable salts thereof, wherein:
R1, R2, R3, and R4 are independently selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, and benzyl; or R1, R2, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group; or R3, R4, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group; or R1, R2, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group and R3, R4, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group, with the proviso that none of R1, R2, R3, or R4 is xe2x80x94(CH2)0-4Cxe2x89xa1CH;
n and m are independent integers ranging from 0 to 4;
K1 and K2 are independently xe2x80x94CH2OH or xe2x80x94OC(O)R5; and
R5 is selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, and benzyl.
The compounds of formula I and pharmaceutically acceptable salts thereof are useful for treating or preventing cardiovascular diseases, dyslipidemias, dyslipoproteinemias, disorders of glucose metabolism, Alzheimer""s Disease, Syndrome X, PAR-associated disorders, septicemia, thrombotic disorders, obesity, pancreatitis, hypertension, renal diseases, cancer, inflammation, or impotence.
In another embodiment, the invention comprises a compound of the formula IV: 
wherein:
n is an integer ranging from 1 to 4;
K1 selected from the group consisting of xe2x80x94CH2OH, xe2x80x94C(O)OH, xe2x80x94CHO, xe2x80x94C(O)OR5, xe2x80x94OC(O)R5, xe2x80x94SO3H, 
R1, and R2 are independently selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, and benzyl; or R1, R2, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group; or R3, R4, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group; or R1, R2, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group and R3, R4, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group, with the proviso that none of R1, R2, R3, or R4 is xe2x80x94(CH2)0-4Cxe2x89xa1CH;
R5 is selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, and benzyl;
each R6 is independently selected from the group consisting of H, (C1-C6)alkyl, (C2-C6)alkenyl, and (C2-C6)alkynyl;
R7 is selected from the group consisting of H, (C1-C6)alkyl, (C2-C6)alkenyl, and (C2-C6)alkynyl; and
W is selected from the group consisting of H, (C1-C6)alkyl, and a hydroxy protecting group.
In another embodiment, the invention provides a compound of the formula V: 
wherein:
n is an integer ranging from 1 to 4;
K1 selected from the group consisting of xe2x80x94CH2OH, xe2x80x94C(O)OH, xe2x80x94CHO, xe2x80x94C(O)OR5, xe2x80x94OC(O)R5, xe2x80x94SO3H, 
R3, and R4 are independently selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, and benzyl; or R1, R2, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group; or R3, R4, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group; or R1, R2, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group and R3, R4, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group, with the proviso that none of R1, R2, R3, or R4 is xe2x80x94(CH2)0-4Cxe2x89xa1CH;
R5 is selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, and benzyl;
each R6 is independently selected from the group consisting of H, (C1-C6)alkyl, (C2-C6)alkenyl, and (C2-C6)alkynyl;
R7 is selected from the group consisting of H, (C1-C6)alkyl, (C2-C6)alkenyl, and (C2-C6)alkynyl; and
Hal is selected from the group consisting of chloro, bromo, and iodo.
The compounds of formulas IV and V are useful as intermediates for synthesizing the compounds of formula I.
In still another embodiment, the invention provides a method for the synthesis of a compound of a formula II: 
comprising (a) contacting in the presence of a base a compound of a formula XXIV: 
with a compound of a formula XXVIII: 
to provide a compound of a formula XXIX: 
and (b) deprotecting the compound of the formula XXIX to provide the compound of the formula II, wherein:
R1, R2, R3, and R4 are independently selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, and benzyl; or R1, R2, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group; or R3, R4, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group; or R1, R2, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group and R3, R4, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group, with the proviso that none of R1, R2, R3, or R4 is xe2x80x94(CH2)0-4Cxe2x89xa1CH; and
PG is a hydroxy protecting group.
In still another embodiment, the invention provides a method for the synthesis of a compound of formula III: 
comprising contacting a compound of a formula of formula VI: 
with a reducing agent, wherein:
R1, R2, R3, and R4 are independently selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, and benzyl; or R1, R2, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group; or R3, R4, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group; or R1, R2, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group and R3, R4, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group, with the proviso that none of R1, R2, R3, or R4 is xe2x80x94(CH2)0-4Cxe2x89xa1CH;
each R10 is independently selected from the group consisting of xe2x80x94H, xe2x80x94OH, (C1-C8)alkoxy, (C6)aryloxy, xe2x80x94Oxe2x80x94(C2-C6)alkenyl, xe2x80x94Oxe2x80x94(C2-C6)alkynyl, halo; and
n and m are independent integers ranging from 0 to 4.
The present invention further provides compositions comprising a compound of the formula I or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable vehicle. These compositions are useful for treating or preventing a disease or disorder selected from the group consisting of a cardiovascular disease, dyslipidemia, dyslipoproteinemia, a disorder of glucose metabolism, Alzheimer""s Disease, Syndrome X, a PPAR-associated disorder, septicemia, a thrombotic disorder, obesity, pancreatitis, hypertension, a renal disease, cancer, inflammation, and impotence. These composition are also useful for reducing the fat content of meat in livestock and reducing the cholesterol content of eggs.
The present invention provides a method for treating or preventing a cardiovascular disease, dyslipidemia, dyslipoproteinemia, a disorder of glucose metabolism, Alzheimer""s Disease, Syndrome X, a PPAR-associated disorder, septicemia, a thrombotic disorder, obesity, pancreatitis, hypertension, a renal disease, cancer, inflammation, and impotence, comprising administering to a patient in need of such treatment or prevention a therapeutically effective amount of a composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable vehicle.
The present invention further provides a method for reducing the fat content of meat in livestock comprising administering to livestock in need of such fat-content reduction a therapeutically effective amount of a composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable vehicle.
The present invention provides a method for reducing the cholesterol content of a fowl egg comprising administering to a fowl species a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable vehicle.
The present invention may be understood more fully by reference to the figures, detailed description, and examples, which are intended to exemplify non-limiting embodiments of the invention.